Aminoalkyloximers

ABSTRACT

Novel aminoalkyloximes, precursors and processes for the preparation thereof, and methods of treating depression and obsessive compulsive disorders are described.

This is a division of application Ser. No. 08/285,668, filed Aug. 3,1994, now U.S. Pat. No. 5,665,756, which is herein incorporated byreference.

The present invention relates to aminoalkyloximes. More particularly,the present invention relates to aminoalkyloximes of formula 1 ##STR1##wherein:

a. X is hydrogen, loweralkyl, loweralkoxy, halogen, trifluoromethyl, ora group of the formula ##STR2## wherein Y is hydrogen or loweralkyl, andp is 1 or 2;

b. A is a group of the formula ##STR3## a group of the formula ##STR4##wherein Y is as above and q is 1 or 2; a group of the formula ##STR5##wherein B is a group of the formula ##STR6## wherein X and p are asabove or a group of the formula ##STR7## wherein R³ is hydrogen orloweralkyl and X and p are as above and r is 1, 2, or 3;

c. R¹ and R² are independently hydrogen or loweralkyl or R¹ and R² takentogether with the nitrogen atom to which they are attached form a groupof the formula ##STR8## wherein W is CH₂, O, or S, r is as above; and sis 1, 2, or 3;

d. m is 2 to 6, inclusive, and n is 0, or 2 to 6, inclusive, thegeometric and optical isomers thereof; or the pharmaceuticallyacceptable salts thereof, which are useful for treating depression andobsessive compulsive disorders, alone or in combination with adjuvants.

Subgeneric thereto are aminoalkyoximes wherein:

a. A is a group of the formula ##STR9##

b. A is a group of the formula ##STR10## and

c. A is a group of the formula ##STR11## and X is ##STR12##

Also included in the present invention are compounds of the formula##STR13## wherein Y is hydrogen or loweralkyl and p is 1 or 2.

As used throughout the specification and appended claims, the term"alkyl" refers to a straight or branched chain hydrocarbon radicalcontaining no unsaturation and having 1 to 8 carbon atoms. Examples ofalkyl groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-hexyl,3-hexyl, 4-heptyl, 2-octyl and the like. The term "alkoxy" refers to amonovalent substituent which consists of an alkyl group linked throughan ether oxygen having its free valence bond from the ether oxygen.Examples of alkoxy groups are methoxy, ethoxy, propoxy, 1-butoxy,1-pentoxy, 3-hexoxy, 4-heptoxy, 2-octoxy and the like. The term"alkanol" refers to a compound formed by a combination of an alkyl groupand hydroxy radical. Examples of alkanols are methanol, ethanol, 1- and2-propanol, 2,2-dimethylethanol, hexanol, octanol and the like. The term"halogen" refers to a member of the family fluorine, chlorine, bromine,or iodine. The term "lower" as applied to any of the aforementionedgroups refers to a group having a carbon skeleton containing up to andincluding 6 carbon atoms.

The compounds of the present invention which lack an element of symmetryexist as optical antipodes and as the racemic forms thereof. The opticalantipodes may be prepared from the corresponding racemic forms bystandard optical resolution techniques, involving, for example, theseparation of diastereomeric salts of those instant compoundscharacterized by the presence of a basic amino group and an opticallyactive acid, or by synthesis from optically active precursors.

The aminoalkyloximes of formula 1 exist in isomeric Z- and E-forms. Forexample, 3-(1H-imidazolyl)propiophenone-O-(2-aminoethyl)oxime exists inthe Z- and E-isomeric forms, 2 and 3, respectively, as shown below:##STR14##

In the Z-isomer, the aminoalkyloxy group of the oxime function and thephenyl moiety, the group of greater priority, are cis to each other andin the E-isomer, the aminoalkyloxy group of the oxime function and thephenyl moiety, are trans to each other. The wiggly (˜) line in theformulas of the aminoalkyloximes of formula 1 indicate that the compoundmay be the E- or Z-isomer. See B. Unterhalt, Methodicum Chimicum 6 403(1975), for a discussion of the E-Z nomenclature.

The present invention comprehends all optical isomers and racemic formsthereof of the compounds disclosed and claimed herein and the formulasof the compounds shown herein are intended to encompass all possibleoptical isomers of the compounds so depicted.

The novel aminoalkyloximes 1 are prepared by condensing a phenone 4 withan aminooxyalkylamine 5 as illustrated below: ##STR15## wherein A, R¹,R², X, m, n, and p are as hereinbeforedescribed. The condensation isgenerally performed by treating a phenone 4 with an aminooxyalkylamine 5as a salt, for example, a dihydrohalide 5a ##STR16## wherein Hal ischloro or bromo, chloro being preferred, in the presence of an acidacceptor, for example, a tertiary amine such as a trialkylamine(trimethylamine, triethylamine, tripropylamine, and the like) or aheteroaromatic amine (pyridine, picoline, lutidine, s-collidine, and thelike), a heteroaromatic amine, namely, pyridine being preferred. Whilethe condensation proceeds readily in the tertiary amine, for example,pyridine, acting as both an acid acceptor and solvent, a cosolvent, forexample, an alkanol such as ethanol may be used to facilitate thereaction. The condensation temperature is not narrowly critical, thecondensation is referably performed at the reflux temperature of thereaction medium.

The requisite phenones 4 and aminooxyalkylamine 5 are prepared by theprocesses shown in the Reaction Scheme. To prepare a phenone 4, forexample, a benzene 6 is treated with a carbonylhalide 7 having a leavinggroup L, i.e., a halo group such as chloro or bromo, or a sulfonyloxygroup such as methylsulfonyloxy, phenylsulfonyloxy, or4-methylphenylsulfonyloxy in the presence of a Friedel-Crafts catalystsuch as aluminum chloride to afford an intermediate phenone 8 which isthen treated with a nucleophile AH 9 in the presence of a base, e.g., atertiary amine (triethylamine or pyridine) or an alkali metal carbonateor -bicarbonate (sodium carbonate or potassium bicarbonate) to yield theultimate phenone 4 by well-known methods.

Alternatively, a phenone 4 is prepared by condensing an alkyne 10 havinga leaving group L wherein L is as described above with a nucleophile AH9 in an aprotic dipolar solvent such as dimethylformamide at atemperature of about 60° to 80° C. to provide a substituted alkyne 11,which is sequentially treated with a halobenzene of the formula 12##STR17## wherein X, p, and Hal are as described above in a condensationmedium of bis(triphenylphosphine) palladium (II) chloride, copper (I)iodide, and triethylamine, and then a hydration medium of sulfuric acidin the presence of mercury (II) sulfate in aqueous ethanol to providephenylalkyne 13 and ultimate phenone 4, respectively. See T. Sakamuto,et al., Chemical and Pharmaceutical Bulletin (Japan) 34, 2754 (1986) andA. N. Tischler and T. J. Lanza, Tetrahedron Letters, 27, 1653 (1986).The aminooxyalkylamines 5 are prepared by treating N-hydroxyphthalimide14 with an N-substituted phthalimide 15 having a leaving group L whereinL is as described above in the presence of an alkali metal carbonate,e.g., potassium carbonate, in an aprotic dipolar solvent, e.g.,dimethylformamide, to form coupled product 16 cleaving the coupledproduct 16 with hydrazine in an alkanol, e.g., ethanol, to provide anaminoalkylhydroxyamine 17 and then alkylating anaminioalkylhydroxylamine 17 with an alkyl halide or -dihalide of theformula 18, 19, or 20 ##STR18## in the presence of a trialkylamine,e.g., triethylamine to yield 5. See Organic Chemistry, D. J. Cram and G.S. Hammond, McGraw-Hill, New York, N.Y., 1959, page 215.

The aminoalkyloxides of the present invention are useful as agents forthe alleviation of depression and affective disorders such as obsessivecompulsive disorders, particularly those associated with serotonergichypofunction. See, for example, W. K. Goodman, et al., Archives ofGeneral Psychiatry, 47, 577 (1990). Alleviation of depression andaffective disorders, including obsessive compulsive disorders, isdemonstrated in the in vitro inhibition of serotonin uptake, an assayfor the determination of the ability of a drug to inhibit the reuptakeof serotonin, a neurotransmitter implicated in the etiology ofdepression and affective disorders. In this assay, a modification of thetests described by A. S. Horn and R. C. A. M. Trace, British Journal ofPharmacology, 51, 399 (1974), A. Nagy and A. V. Delgado-Escueta, Journalof Neurochemistry, 43, 1114 (1984) and P. R. Dunkley, et al., BrainResearch, 372, 115 (1986), the following reagents are prepared andemployed:

Procedure:

A. Animals

Male CR Wistar rats (100-125 g)

B. Reagents

1. Krebs-Heniseleit Bicarbonate Buffer, pH 7.4 (KHBB):

Prepare a 1 liter batch, containing the following salts.

    ______________________________________                                                           grams/L mM                                                 ______________________________________                                        NaCl                 6.92      118.4                                          KCl                  0.35      4.7                                            MgSO.sub.4.7H.sub.2 O                                                                              0.29      1.2                                            KH.sub.2 PO.sub.4    0.16      2.2                                            NaHCO.sub.3          2.10      24.9                                           CaCl.sub.2           0.14      1.3                                            Prior to use add to 200 ml, per assay:                                        Dextrose               2 mg/ml 11.1                                           Iproniazid phosphate 0.30 mg/ml                                                                              0.1                                            ______________________________________                                    

The batch is aerated for 60 minutes with 95% oxygen/5% carbon dioxide,the pH is checked to insure it is at 7.4±0.1, then add bovine serumalbumin (Sigma cat# A-7906) 1 mg/ml.

2. Filtration buffer:

Make a 4 liter batch containing the following salts:

    ______________________________________                                                      grams/4 L                                                                            mM                                                       ______________________________________                                        NaCl            31.68    135.5                                                KCl              1.40    4.7                                                  MgSO.sub.4.7H.sub.2 O                                                                          1.16    1.2                                                  HEPES            9.54    10.0                                                 CaCl.sub.2       0.56    1.3                                                  BSA             4.0      1 mg/ml                                              ______________________________________                                    

Maintain on ice.

3. Sucrose solution: 0.32M sucrose containing 5 mM HEPES and 0.1 mMEDTA; pH to 7.3 using Tris base.

4. A 0.1 mM stock solution of serotonin creatinine SO₄ is made up in0.01N HCl. This is used to dilute the specific activity of radiolabeled5HT.

5. 5- 1,2-³ H(N)!-Hydroxytryptamine creatinine sulfate (serotonin),specific activity 20-30 Ci/mmol, is used.

The final desired concentration of ³ H!-5HT in the assay is 50 nM. Thedilution factor is 0.8. The KHBB is made up to contain 62.5 nM of ³H!-5HT.

Add to 100 ml of KHBB:

    ______________________________________                                        A)         56.1 μl of 0.1 mM 5HT =                                                                   56.1 nM                                             B)         0.64 nmol of  .sup.3 H!-5HT =                                                                 6.4 nM                                                                       62.5 nM                                             ______________________________________                                    

6. For most assays, a 0.5 mM stock solution of the test compound is madeup initially in either 10 μl of glacial acetic acid, 100 μl DMSO or 10μl of the recrystallization solvent, to which is added approximately 10ml of distilled water. Compounds are initially screened in duplicate at3 concentrations (10⁻⁸, 10⁻⁷ and 10⁻⁶ M) made up in water. For thosecompounds demonstrating activity at ≦10⁻⁷ in the initial screen, IC₅₀ Sare determined from 7 concentrations: 10⁻⁹ through 10⁻⁶. Higher or lowerconcentration ranges may be used depending on the potency of thecompound. To ensure consistency, the standard clomipramine is run witheach assay.

C. Tissue Preparation

Male Wistar rats are decapitated and the brain rapidly removed. Wholebrain (minus cerebellum) is weighed and homogenized in 15 volumes of icecold sucrose solution using a Potter-Elvejhem homogenizer. The followingprocedures are performed on ice. Homogenization should be done with 4-5up and down strokes at medium speeds (setting 4.5 to 5) to minimizesynaptosome lysis. The homogenate is centrifuged at 1000 g (3000 rpm,Sorvall SS-34 rotor) for 10 minutes at 0°-4° C. The supernatant isremoved and approximately 10 ml per tube is carefully layered onto adiscontinuous Percoll (Sigma cat# P-1644) gradient: 21% Percoll insucrose solution at the bottom (15 ml per tube) and 10% Percoll in themiddle (10 ml; colored with a few drops of phenol red for visibility).

The Percoll gradient tubes are carefully placed into a Beckman SW-28swinging bucket rotor and spun in a Beckman XL90 ultracentrifuge usingthe following program: speed, 11,000 rpm ( 5,000 g) for 30 minutes at 4°C.; slow acceleration and deceleration (acceleration setting 9;deceleration setting 3). Tubes are carefully removed, and the top layerand the top part of the middle (red) layers are discarded using apasteur pipette. The synaptosomes are located in the white fluffy bandat the interface between the 10% and 21% Percoll layers. This iscarefully removed, placed in a centrifuge tube, diluted with KHBB andspun at 21,000 g (13,000 rpm, Sorvall SS-34 rotor). The pellet(synaptosomes) is resuspended in KHBB (10 vol per grain original brainwet weight; 1 brain minus cerebellum weighs approximately 1.2 g; 2.5brains are needed per typical assay).

    ______________________________________                                        D.     Assay                                                                  ______________________________________                                        800 μl        KHBB with  .sup.3 H!-5HT                                      20 μl        Vehicle or appropriate drug                                  200 μl        Tissue suspension concentration                              ______________________________________                                    

200 of the tissue suspension are added to each of 24 tubes (at a time)containing the 20 μl of vehicle or drug on ice. Three minutes later, 800μl of KHBB containing ³ H!-5HT are added, and tubes are vortexed. Therack containing the 24 tubes is moved from the ice bath to a water bathset at 37° C. The tubes are incubated for 5 minutes under 95% oxygen/5%carbon dioxide. Uptake is terminated by filtration through GF/B filterstrips using a Brandel cell harvester (filter strips are presoaked inice cold filtration buffer). Tubes are washed once with 5 mil of icecold filtration buffer. Filter disks are placed in scintillation vialsto which are added 10 ml of scintillation fluid (EcoScint). Filters areallowed to sit overnight before being counted.

For each assay, 3 tubes are incubated with 20 μl of vehicle at both 37°C. and 0° C. Active uptake is the difference between cpm taken up at 37°C. and 0° C. Percent inhibition at each concentration is the mean of twodeterminants. IC₅₀ values are derived from log probit analysis using #46Litchfield and Wilcoxon I: confidence limits of IC₅₀ PharmacologicCalculation System--version 4.0.

                  TABLE A                                                         ______________________________________                                                                Inhibition of                                                                 Serotonin Reuptake                                    Compound                Activity IC.sub.50 (μM)                            ______________________________________                                        4'-Chloro-3-(1-(1H)-imidazolyl)propiophenone-                                                         0.128                                                 O-(2-aminoethyl)oxime                                                         4'-Methoxy-3-(1-(1H)-imidazolyl)propiophenone-                                                        1.28                                                  O-(2-aminoethyl)oxime                                                         4'-(1-(1H)-imidazolyl)-1-phenyl-1-butanone                                                            1.81                                                  O-(2-aminoethyl)oxime                                                         3-(1-(1H)-imidazolyl)-1-(4-trifluoromethyl-                                                           0.164                                                 phenyl)-1-propanone O-(2-aminoethyl)oxime                                     1-(4-chlorophenyl)-4-(1-(1H)-imidazolyl)-1-                                                           0.160                                                 butanone O-(2-aminoethyl)oxime                                                1-(4-fluorophenyl)-4-(1-(1H)-imidazolyl)-                                                             0.257                                                 1-butanone O-(2-aminoethyl)oxime                                              4-(2-methyl-1-(1H-)imidazolyl-1-phenyl-1-                                                             0.656                                                 butanone O-(1-aminoethyl)oxime                                                4-(1-(1H)-imidazolyl)-1-(4-trifluoromethyl                                                            0.080                                                 phenyl)-1-butanone O-(2-aminoethyl)oxime                                      Amitriptyline (standard)                                                                              0.091                                                 Fluoxetine (standard)   0.042                                                 ______________________________________                                    

Alleviation of depression and affective disorders is achieved when thepresent aminoalkyoximes are administered to a subject requiring suchtreatment as an effective oral, parenteral or intravenous dose of from0.01 to 100 mg/kg of body weight per day. A particularly effectiveamount is about 25 mg/kg of body weight per day. It is to be understood,however, that for any particular subject, specific dosage regimensshould be adjusted according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the aforesaid compound. It is to be further understood that thedosages set forth herein are exemplary only and that they do not, to anyextent, limit the scope or practice of the invention.

Compounds of the invention include:

a. 3-(1-(1H)-imidazolyl)-1-(2-methoxyphenyl)-1-propanoneO-(2-aminoethyl)oxime;

b. 3-(1-(1H)-imidazolyl)-1-(2-methylphenyl)-1-propanoneO-(2-aminoethyl)oxime;

c. 3-(2,4-dimethyl-(1H)-imidazolyl)propiophenone O-(2-aminoethyl)oxime;

d. 4- 4-(3-methylbenzoyl)-1-piperidinyl!-1-phenyl-1-butanoneO-(2-aminoethyl)oxime;

e. 4- 4-(2,4-dimethylbenzoyl)-1-piperidinyl!-1-phenyl-1-butanoneO-(2-aminoethyl)oxime;

f. 4- 4-(4-methoxybenzoyl)-1-piperidinyl!-1-phenyl-1-butanoneO-(2-aminoethyl)oxime;

g. 4- 4-(4-trifluoromethylbenzoyl)-1-piperidinyl!-1-phenyl-1-butanoneO-(2-aminoethyl)oxime;

h. 4- 4-(benzoyl)-1-piperidinyl!-1-phenyl-1-butanoneO-(2-aminoethyl)oxime;

i. 4- 3-(4-fluorobenzoyl)-1-pyrrolidinyl!-1-phenyl-1-butanoneO-(2-aminobutyl)oxime;

j. 4- 4-(4-fluorobenzoyl)-1-hexahydroazepinyl!-1-phenyl-1-butanoneO-(2-aminoethyl)oxime;

k. 1-(1-4-(2-aminoethoxyimino)-4-(4-chlorophenyl)butyl!-4-piperidinyl)-1,3-dihydro-3-methyl-2-benzimidazolone;

l. 3-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-propanone O-2-(1-piperidinyl)ethyl!oxime;

m. 3-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-propanone O-2-(1-pyrrolidinyl)ethyl!oxime;

i. 3-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-propanone O-2-(1-hexahydroazepinyl)ethyl!oxime;

o. 3-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-propanone O-2-(1-morpholinyl)ethyl!oxime; and

p. 3-(1-1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-propanone O-2-(1-thiomorpholinyl)ethyl!oxime.

Effective amounts of the compounds of the invention may be administeredto a subject by any one of various methods, for example, orally as incapsules or tablets, parenterally in the form of sterile solutions orsuspensions, and in some cases a intravenously in the form of sterilesolutions. The free base final products, while effective themselves, maybe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility and the like.

Preferred pharmaceutically acceptable addition salts include salts ormineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid, oxalicacid and the like, and salts of tribasic carboxylic acids such as, forexample, carboxysuccinic acid, citric acid and the like.

The active compounds of the present invention may be administeredorally, for example, with an inert diluent or with a edible carrier.They may be enclosed in gelatin capsules or compressed into tablets. Forthe purpose of oral therapeutic administration, the aforesaid compoundsmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 75% of the weight of the unit. Theamount of present compound in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording o the present invention are prepared so that an oral dosageunit form contains between 1.0-300 mgs of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotes; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl, salicylate,or orange flavoring may be added. When the dosage unit is a capsule, itmay contain, in addition to materials of the above type, a liquidcarrier such as fatty oil. Either dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent acertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of theaforesaid compound, but may be varied between 0.5 and about 50% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mgs of the activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

The following examples are for illustrative purposes only and are not tobe construed as limiting the invention.

EXAMPLE 1

3-1-(1H)-Imidazolyl)propiophenone-O-(2-aminoethyl)oxime difumarate

A mixture of 3-((1H)-imidazolyl)propiophenone (2.74 g),2-aminooxyethylamine dihydrochloride (2.65 g), and pyridine (100 mL) washeated under reflux, under nitrogen, for two hrs. The reaction mixturewas concentrated, and the residue was pumped under high vacuum and thenflash chromatographed (1:1:18 triethylamine/methanol/dichloromethane,then 1:1:8 triethylamine/methanol/dichloromethane). The appropriatefractions were collected and concentrated. The residue was distributedbetween 10% sodium hydroxide solution and ethyl acetate. The layers wereseparated, and the organic layers were dried over anhydrous magnesiumsulfate, filtered, and the filtrate was concentrated and pulped underhigh vacuum, at steam bath temperature. To the residue in methanol wasadded fumaric acid (2.04 g), then ethyl acetate, carefully, toprecipitate the salt. The solid was collected and dried under highvacuum at 56° C. The solid was slurried in a small amount of methanol toyield 1.02 g (15.2%) of product, mp 130.5°-132° C., after drying underhigh vacuum for four hrs at 97° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.14 H.sub.18 N.sub.4 O.C.sub.8 H.sub.8 O.sub.8                              53.88% C 5.34% H  11.42% N                                  Found:            53.44% C 5.30% H  11.36% N                                  ______________________________________                                    

EXAMPLE 2

3-(1-(1H)-Imidazol)-1-(4-trifluoromethylphenyl)-1-propanoneO-(2-aminoethyl)oxime dihydrochloride

A mixture of3-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-propanone (4.65 g),O-(2-aminoethyl)hydroxylamine dihydrochloride (3.10 g), 3 equivalents ofpyridine, and absolute ethanol (75 nil) was heated under reflux, undernitrogen, with stirring, for two hrs. The reaction mixture was dilutedwith 10% sodium hydroxide solution and ethyl acetate. The layers wereseparated. The aqueous phase was extracted with ethyl acetate, theorganic layers were dried over anhydrous sodium sulfate, filtered, andthe filtrate was evaporated. The residue was taken up in toluene andevaporated. The residue was flash chromatographed (180:19:1dichloromethane/methanol/ammonium hydroxide). The appropriate fractionswere collected and concentrated. The residue was dissolved in absoluteethanol and treated with ethereal hydrogen chloride. Diethyl ether wasadded to the solution. The solid was collected and recrystallized twicefrom absolute ethanol/ether to give 2.8 g (40%) of product, mp 213°-214°C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.15 H.sub.19 Cl.sub.2 F.sub.3 N.sub.4 O:                                  45.13% C  4.80% H  14.03% N                                   Found:          44.82% C  4.69% H  13.98% N                                   ______________________________________                                    

EXAMPLE 3

3-(1-(1H)-Imidazolyl)-1-(3-trifluoromethylphenyl)-1-propanoneO-(2-amimoethyl)oxime dihydrochloride

A mixture of3-(1-(1H)-imidazolyl)-1-(3-trifluoromethylphenyl)-1-propanone (4.60 g),O-(2-aminoethyl)hydroxylamine dihydrochloride (3.07 g), 3 equivalents ofpyridine, and absolute ethanol (75 ml) was stirred under reflux, undernitrogen, for three hrs. The reaction mixture was diluted with 10%sodium hydroxide solution and ethyl acetate. The layers were separated.The aqueous phase was extracted with ethyl acetate, the organic layerswere dried over anhydrous sodium sulfate, filtered, and the filtrate wasevaporated. The residue was taken up in toluene and evaporated. Theresidue was flash chromatographed (180:19:1dichloromethane/methanol/ammonium hydroxide). The appropriate fractionswere collected and concentrated. The residue was dissolved in absoluteethanol and treated with ethereal hydrogen chloride. Diethyl ether wasadded to the solution. The solid was collected and recrystallized twicefrom absolute ethanol/ether to give 2.2 g (32%) of product, mp 223°-225°C. (dec.)

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.15 H.sub.19 Cl.sub.2 F.sub.3 N.sub.4 O:                                  45.13% C  4.80% H  14.03% N                                   Found:          45.19% C  4.69% H  13.99% N                                   ______________________________________                                    

EXAMPLE 4 4'-Methoxy-3-(1-(1H)-imidazolyl)propiophenoneO-(2-aminoethyl)oxime difumarate hydrate

A mixture of 4'-methoxy-3-(1H)-imidazolyl)propiophenone (1.47 g),2-aminooxyethylamine dihydrochloride (1.14 g), ethanol (50 mL), andpyridine (1.55 mL) was heated under reflux, under nitrogen, for six hrs.The reaction mixture was concentrated, pumped under high vacuum, and theresidue was flash chromatographed (1:1:8triethylamine/methanol/dichloromethane). The appropriate fractions werecollected and concentrated, and the residue was pimped under high vacuumat 100° C. The residue was distributed between 10% sodium hydroxidesolution and ethyl acetate. The organic layers were dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. To theresidue in methanol was added fumaric acid (1.26 g), then ethyl acetate,carefully, to precipitate the salt. The precipitate was collected undernitrogen and dried under high vacuum at 56° C. for five hrs. The residuewas triturated with pentane and dried under high vacuum at 56° C. togive 1.06 g (30.8%) of product, mp 88°-90° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for  51.30% C  5.62% H  10.40% N                                   C.sub.15 H.sub.20 N.sub.4 O.sub.2.C.sub.8 H.sub.8 O.sub.8 --H.sub.2 O:        Found:          51.01% C  5.51% H  10.29% N                                   ______________________________________                                    

EXAMPLE 5

4'-Methoxy-3-(2-methyl-1-(1H)-imidazolyl)propiophenoneO-(2-aminoethyl)oxime difumarate

A mixture of 4'-methoxy-3-(2-methyl-1-(1H)-imidazolyl)propiophenone(1.67 g), 2-aminooxyethylamine dihydrochloride (1.23 g), ethanol (60mL), and pyridine (2.0 mL), was heated under reflux, under nitrogen, fortwo hrs. The reaction mixture was concentrated, pumped tinder highvacuum, and flash chromatographed (1:1:8triethylamine/methanol/dichloromethane). The appropriate fractions werecollected and concentrated. The residue was distributed between 10%sodium hydroxide solution and ethyl acetate. The layers were separatedand the organic layers were dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated and pumped under high vacuumat 100° C. To the residue in methanol was added fumaric acid (1.29 g),then ethyl acetate, carefully, to precipitate the salt. The precipitatewas recrystallized from methanol and ethyl acetate and dried under highvacuum at 97° C. to yield 2.08 g (56.7%) of product, mp 168°-169° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.16 H.sub.22 N.sub.4 O.sub.2.C.sub.8 H.sub.8 O.sub.8      :                 53.93% C 5.66% H  10.48% N                                  Found:            53.97% C 5.57% H  10.27% N                                  ______________________________________                                    

EXAMPLE 6

4'-Chloro-3-(1-(1H)-imidazolyl)propiophenone O-(2-aminoethyl)oximedifumarate

A mixture of 4'-chloro-3-(1-(1H)-imidazolyl)propiophenone (1.7 g),2-aminooxyethylamine dihydrochloride (1.4 g), and pyridine (50 mL), washeated under reflux, under nitrogen, for four hrs. The reaction mixturewas concentrated, pumped under high vacuum, and the residue was flashchromatagraphed (1:1:18 triethylamine/methanol/dichloromethane). Theappropriate fractions were collected and concentrated. The residue wasdistributed between 10% sodium hydroxide solution and ethyl acetate. Thelayers were separated and the organic layers were dried over anhydrousmagnesium sulfate, filtered and the filtrate was concentrated, andpumped under high vacuum, at 100° C. for one hr. To the residue inmethanol was added fumaric acid (1.29 g), then ethyl acetate, carefully,to precipitate the salt. The precipitate was dried under high vacuum at97° C. to yield 2.23 g (58.8%) of product, hip 153°-153.5° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for                                                                              50.34% C   4.80% H  10.67% N                                    C.sub.14 H.sub.17 N.sub.4 OCl.C.sub.8 H.sub.8 O.sub.8 :                       Found:        50.29% C   4.89% H  10.49% N                                    ______________________________________                                    

EXAMPLE 7

4'-Chloro-3-(2-methyl-1-(1H)-imidazolyl)propiophenoneO-(2-aminoethyl)oxime sesquifumarate

A mixture of 4'-chloro-3-(2-methyl-1-(1H)-imidazolyl)propiophenone (3.56g), 2-aminooxyethylamine dihydrochloride (2.77 g), and pyridine (150 mL)was heated under reflux, under nitrogen, for two hrs. The reaction wasconcentrated, pumped under high vacuum, and flash chromatographed(1:1:18 triethylamine/methanol/dichloromethane, then 1:1:8triethylamine/methanol/dichloromethane). The appropriate fractions werecollected and concentrated. The residue was distributed between 10%sodium hydroxide solution and ethyl acetate. The layers were separatedand the organic layers were dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated and pumped under highvacuum. To the residue in methanol was added fumaric acid (1.7 g), thenethyl acetate, carefully, to precipitate the salt. The precipitate wascollected and recrystallized from methanol and ethyl acetate and driedunder high vacuum at 111° C. to yield 2.97 g (43.2%) of product, mp179°-180° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for                                                                              52.45% C   5.24% H  11.65% N                                    C.sub.15 H.sub.19 N.sub.4 OCl.C.sub.6 H.sub.6 O.sub.6 :                       Found:        52.05% C   5.27% H  11.30% N                                    ______________________________________                                    

EXAMPLE 8

3-(2-Methyl-1-(1H)-imidazolyl)propiophenone O-(2-aminoethyl)oximedifumarate

A mixture of 3-(2-methyl-1-(1H)-imidazolyl)propiophenone (4.0 g),2-aminooxyethylamine dihydrochloride (3.34 g), and pyridine (200 mL) washeated under reflux, under nitrogen, for one hr. Additional amine (175mg) was added, and the mixture was heated for one-half hr. The reactionmixture was concentrated, pumped under high vacuum, and the residue wasflash chromatographed (1:1:18 triethylamine/methanol/dichloromethane,then 1:1:8 triethylamine/methanol/dichloromethane). The appropriatefractions were collected and concentrated. The residue was distributedbetween 1% sodium hydroxide solution and ethyl acetate. The layers wereseparated and the organic layers were dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated and pumped underhigh vacuum. To the residue in methanol was added fumaric acid (1.68 g),then ethyl acetate, carefully, to precipitate the salt. The precipitatewas dried under high vacuum at 78° C. to yield 2.63 g (28. 1%) ofproduct, mp 138° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.15 H.sub.20 N.sub.4 O.C.sub.8 H.sub.8 O.sub.8                              54.76% C 5.59% H  11.11% N                                  Found:            54.67% C 5.57% H  10.91% N                                  ______________________________________                                    

EXAMPLE 9

1-(4-Fluorophenyl)-3-(1-(1H)-imidazolyl)-1-propanoneO-(2-aminoethyl)oxime dihydrochloride

A mixture of 1-(4-fluorophenyl)-3-(1-(1H)-imidazolyl)-1-propanone (3.00g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.46 g), 3equivalents of pyridine and absolute ethanol (75 ml) was heated underreflux, under nitrogen, with stirring, for two hrs. The reaction mixturewas partitioned between 20% sodium hydroxide solution and ethyl acetate.The layers were separated, and the aqueous phase was extracted withethyl acetate. The combined organic extracts were dried over anhydroussodium sulfate, filtered, and the filtrate was evaporated. The residuewas taken up in toluene and evaporated. The residue was purified byflash chromatography (180:19:1 dichloromethane/methanol/ammoniumhydroxide). The appropriate fractions were collected and concentrated.The residue was dissolved in absolute ethanol and treated with etherealhydrogen chloride. Diethyl ether was added. The precipitate wascollected and recrystallized twice from absolute ethanol/ether to give1.9 g (40%) of product, mp 225°-226° C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.14 H.sub.19 Cl.sub.2 FN.sub.4 O:                                         48.15% C  5.48% H  16.04% N                                   Found:          48.34% C  5.54% H  16.04% N                                   ______________________________________                                    

EXAMPLE 10

4-(1-(1H)-Imidazolyl)-1-phenyl-1-butanone O-(2-aminoethyl)oximedihydrochloride

A mixture of 4-(1-(1H)-imidazolyl)-1-phenyl-1-butanone (3.00 g),O-(2-aminoethyl)hydroxylamine dihydrochloride (2.50 g), 3 equivalents ofpyridine, and absolute ethanol (75 ml) was heated under reflux, undernitrogen, with stirring, overnight. The reaction mixture was evaporated,toluene was added and evaporated. The residue was partitioned between10% sodium hydroxide solution and ethyl acetate. The layers wereseparated and the aqueous phase extracted with ethyl acetate. Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and the filtrate was evaporated. The residue was combined with5.0 g of crude, previously prepared material and purified by flashchromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide).The appropriate fractions were collected and concentrated. The residuewas dissolved in absolute ethanol and treated with ethereal hydrogenchloride. Diethyl ether was added. The precipitate was collected andrecrystallized from absolute ethanol to give 6.3 g (58%) of product, mp196°-198° C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.15 H.sub.22 Cl.sub.2 N.sub.4 O:                                          52.18% C  6.42% H  16.23% N                                   Found:          52.28% C  6.18% H  16.18% N                                   ______________________________________                                    

EXAMPLE 11

4-(2-Methyl-1-(1H)-imidazolyl)-1-phenyl-1-butanone O-(2-aminoethyl)oximedihydrochloride

A mixture of 4-(2-methyl-1-(1H)-imidazolyl)-1-phenyl-1-butanone (3.00g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.35 g), 3equivalents of pyridine, and absolute ethanol (75 ml) was heated underreflux, under nitrogen, with stirring, for four hrs. The solvent wasevaporated, toluene was added and evaporated. The residue waspartitioned between 10% sodium hydroxide solution and ethyl acetate. Thelayers were separated and the aqueous phase extracted with ethylacetate. The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, and the filtrate was evaporated. The residue waspurified by flash chromatography (180:19:1dichloromethane/methanol/ammonium hydroxide). The appropriate fractionswere collected and concentrated. The residue was dissolved in absoluteethanol and treated with ethereal hydrogen chloride. Diethyl ether wasadded. The precipitate was collected and recrystallized from absoluteethanol/ether to give 3.1 g (66%) of product, mp 153°-155° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.16 H.sub.24 Cl.sub.2 N.sub.4 O:                                          53.49% C  6.73% H  15.59% N                                   Found:          53.39% C  6.79% H  15.47% N                                   ______________________________________                                    

EXAMPLE 12

1-(4-Chlorophenyl)-4-(1-(1H)-imidazolyl)-1-butanoneO-(2-aminoethyl)oxime dihydrochloride

A mixture of 1-(4-chlorophenyl)-4-(1-(1H)-imidazolyl)-1-butanone (2.20g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.58 g), 3equivalents of pyridine, and absolute ethanol (75 ml) was scaled underreflux, under nitrogen, with stirring, for two hrs. The reaction mixturewas partitioned between 10% sodium hydroxide solution and ethyl acetate.The layers were separated and the aqueous phase extracted with ethylacetate. The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, and the filtrate was evaporated. The residue wastaken up in toluene and evaporated. The residue was purified by flashchromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide).The appropriate fractions were collected and concentrated. The residuewas dissolved in absolute ethanol and treated with ethereal hydrogenchloride. Diethyl ether was added. The precipitate was collected andrecrystallized twice from absolute ethanol/ether to give 1.3 g (39%) ofproduct, mp 205°-207° C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.15 H.sub.21 Cl.sub.3 N.sub.4 O:                                          47.45% C  5.57% H  14.75% N                                   Found:          46.75% C  5.84% H  14.40% N                                   ______________________________________                                    

EXAMPLE 13

4-(1-(1H)-Imidazolyl)-1-(4-trifluoromethylphenyl)-1-butanoneO-(2-aminoethyl)oxime dihydrochloride

A mixture of4-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-butanone (5.00 g),O-(2-aminoethyl)hydroxylamine dihydrochloride (3.17 g), 3 equivalents ofpyridine, and absolute ethanol (75 ml) was heated under reflux, undernitrogen, with stirring, for two hrs. The reaction mixture wasevaporated, toluene was added and evaporated. The residue waspartitioned between 10% sodium hydroxide solution and ethyl acetate. Thelayers were separated and the aqueous phase extracted with ethylacetate. The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, and the filtrate was evaporated. The residue waspurified by flash chromatography (180:19:1dichloromethane/methanol/ammonium hydroxide). The appropriate fractionswere collected and concentrated. The residue was dissolved in absoluteethanol and treated with ethereal hydrogen chloride. Diethyl ether wasadded. The precipitate was collected and recrystallized twice fromabsolute ethanol/ether to give 3.1 g (42%) of product, mp 207°-208° C.(dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.16 H.sub.21 Cl.sub.2 F.sub.3 N.sub.4 O:                                  46.50% C  5.12% H  13.56% N                                   Found:          46.29% C  4.97% H  13.67% N                                   ______________________________________                                    

EXAMPLE 14

4-(2-Methyl-1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-butanoneO-(2-aminoethyl)oxime dihydrochloride

A mixture of4-(2-methyl-1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-butanone(2.65 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.60 g), 3equivalents of pyridine, and absolute ethanol (75 nil) was heated underreflux, under nitrogen, with stirring, for three hrs. The reactionmixture was diluted with 10% sodium hydroxide solution and ethylacetate. The layers were separated. The aqueous phase was extracted withethyl acetate. The organic layers were dried over anhydrous sodiumsulfate, filtered, and the filtrate was evaporated. The residue wastaken up in toluene and evaporated. The residue was purified by flashchromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide).The appropriate fractions were collected and concentrated. The residuewas dissolved in absolute ethanol and treated with ethereal hydrogenchloride. Diethyl ether was added. The precipitate was collected andrecrystallized from absolute ethanol/ether to give 1.4 g (37%) ofproduct, mp 181°-184° C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.17 H.sub.23 Cl.sub.2 F.sub.3 N.sub.4 O:                                  47.79% C  5.43% H  13.11% N                                   Found:          47.45% C  5.43% H  13.05% N                                   ______________________________________                                    

EXAMPLE 15

1-(4-Fluorophenyl)-4-(1-(1H)-imidazolyl)-1-butanoneO-(2-aminoethyl)oxime dihydrochloride

A mixture of 1-(4-fluorophenyl)-4-(1-(1H)-imidazolyl)-1-butanone (3.00g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.31 g), 3equivalents of pyridine, and absolute ethanol (75 ml) was heated underreflux, under nitrogen, with stirring, for four hrs. The reactionmixture was evaporated, toluene was added and evaporated. The residuewas partitioned between 10% sodium hydroxide solution and ethyl acetate.The layers were separated and the aqueous phase extracted with ethylacetate. The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, and the filtrate was evaporated. The residue waspurified by flash chromatography (180:19:1dichloromethane/methanol/ammonium hydroxide). The appropriate fractionswere collected and concentrated. The residue was dissolved in absoluteethanol and treated with ethereal hydrogen chloride. Diethyl ether wasadded. The precipitate was collected and recrystallized from absoluteethanol to give 3.2 g (68%) of product, mp 237°-238° C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.15 H.sub.21 Cl.sub.2 FN.sub.4 O:                                         49.60% C  5.83% H  15.42% N                                   Found:          49.69% C  5.60% H  15.47% N                                   ______________________________________                                    

EXAMPLE 16

1-(4-FIluorophenyl)-4-(2-methyl-1-(1H)-imidazolyl)-1-butanoneO-(2-aminoethyl)oxime dihydrochloride

A mixture of1-(4-fluorophenyl)-4-(2-methyl-1-(1H)-imidazolyl)-1-butanone (3.00 g),O-(2-aminoethyl)hydroxylamine dihydrochloride (2.18 g), 3 equivalents ofpyridine, and absolute ethanol (75 ml) was heated tinder reflux, undernitrogen, with stirring, for three hrs. The reaction mixture wasevaporated, toluene was added and evaporated. The residue waspartitioned between 10% sodium hydroxide solution and ethyl acetate. Thelayers were separated and the aqueous phase extracted with ethylacetate. The combined organic extracts were dried over anhydrous sodiumsulfate, filtered, and the filtrate was evaporated. The residue waspurified by flash chromatography (180:19:1dichloromethane/methanol/ammonium hydroxide). The appropriate fractionswere collected and concentrated. The residue was dissolved in absoluteethanol and treated with ethereal hydrogen chloride. Diethyl ether wasadded. The precipitate was collected and recrystallized from absoluteethanol/ether to give 3.2 g (70%) of product, mp 219°-221° C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.16 H.sub.23 Cl.sub.2 FN.sub.4 O:                                         50.94% C  6.14% H  14.85% N                                   Found:          51.01% C  6.22% H  14.78% N                                   ______________________________________                                    

EXAMPLE 17

1-(3,4-Dichlorophenyl)-4-(1-(1H)-imidazolyl)-1-butanoneO-(2-aminoethyl)oxime dihydrochloride

A mixture of 1-(3,4-dichlorophenyl)-4-(1-(1H)-imidazolyl)-1-butanone(2.29 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.45 g), 3equivalents of pyridine, and absolute ethanol (75 ml) was heated underreflux, under nitrogen, with stirring, for three hrs. The reactionmixture was partitioned between 1% sodium hydroxide solution and ethylacetate. The layers were separated and the aqueous phase extracted withethyl acetate. The combined organic extracts were dried over anhydroussodium sulfate, filtered, and the filtrate was evaporated. The residuewas taken up in toluene and evaporated. The residue was purified byflash chromatography (180:19:1 dichloromethane/methanol/ammoniumhydroxide). The appropriate fractions were collected and evaporated. Theresidue was dissolved in absolute ethanol and treated with etherealhydrogen chloride. Diethyl ether was added. The precipitate wascollected and recrystallized twice from absolute ethanol/ether to give1.1 g (33%) of product, mp 205°-208° C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.15 H.sub.20 Cl.sub.4 N.sub.4 O:                                          43.50% C  4.87% H  13.53% N                                   Found:          43.53% C  4.78% H  13.46% N                                   ______________________________________                                    

EXAMPLE 18

5-(1-(1H)-Imidazolyl)-1-(4-trifuoromethylphenyl)-1-pentanoneO-(2-aminoethyl)oxime dihydrochloride

A mixture of 5-1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-pentanone (11.5 g), O-(2-aminoethyl)hydroxylamine dihydrochloride(5.78 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) washalted under reflux, under nitrogen, with stirring, for three hrs. Thereaction mixture was partitioned between 10% sodium hydroxide solutionand ethyl acetate. The layers were separated and the aqueous phaseextracted with ethyl acetate. The combined organic extracts were driedover anhydrous sodium sulfate, filtered, and the filtrate wasevaporated. The residue was taken up in toluene and evaporated. Theresidue was purified by flash chromatography (180:19:1dichloromethane/methanol/ammonium hydroxide). The appropriate fractionswere collected and evaporated. The residue was dissolved in absoluteethanol and treated with ethereal hydrogen chloride. Diethyl ether wasadded. The precipitate was collected and recrystallized twice fromabsolute ethanol/ether to give 3.3 g (20%) of product, mp 115°-120° C.(dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.17 H.sub.23 Cl.sub.2 F.sub.3 N.sub.4 O:                                  47.79% C  5.43% H  13.11% N                                   Found:          46.99% C  5.39% H  12.83% N                                   ______________________________________                                    

EXAMPLE 19

4- 4-(4-Fluorobenzoyl)-1-piperidinyl!-1-phenyl-1-butanoneO-(2-aminoethyl)oxime dihydrochloride

A mixture of 4- 4-(4-fluorobenzoyl)-1-piperidinyl!-1-phenyl-1-butanone(5.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.21 g), 3equivalents of pyridine, and absolute ethanol (75 ml) was stirred at 60°C., overnight, tinder nitrogen. The reaction mixture was evaporated,toluene was added and evaporated. The reaction mixture was partitionedbetween 10% sodium hydroxide solution and ethyl acetate. The layers wereseparated and the aqueous phase extracted with ethyl acetate. Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and the filtrate was evaporated. The residue was purified byflash chromatography (180:19:1 dichloromethane/methanol/ammoniumhydroxide). The appropriate fractions were collected and evaporated. Theresidue was dissolved in absolute ethanol and treated with etherealhydrogen chloride. Diethyl ether was added. The precipitate wascollected and recrystallized twice from absolute ethanol/ether to give2.3 g (34%) of product, mp 110°-115° C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.24 H.sub.32 Cl.sub.2 FN.sub.3 O.sub.2 :                                  59.50% C  6.66% H  8.67% N                                    Found:          59.18% C  6.96% H  8.69% N                                    ______________________________________                                    

EXAMPLE 20

1-{1-4-(2-Aminoethoxyimino)-4-(4-chlorophenyl)butyl!-4-piperidinyl}-1,3-dihydro-2-benzimidazolonedihydrochloride

A mixture of 1- 1-4-oxo-4-(4-chlorophenyl)butyl!-4-piperidinyl)-1,3-dihydro-2-benzimidazolone(3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.35 g), 3equivalents of pyridine, and absolute ethanol (75 nil) was heated underreflux, under nitrogen, with stirring, for three hrs. The reactionmixture was partitioned between 10% sodium hydroxide solution and ethylacetate. The layers were separated and the aqueous phase extracted withethyl acetate. The combined organic extracts were dried over anhydroussodium sulfate, filtered, and the filtrate was evaporated. The residuewas taken up in toluene and evaporated. The residue was purified byflash chromatography (180:19:1 dichloromethane/methanol/ammoniumhydroxide). The appropriate fractions were collected and evaporated. Theresidue was dissolved in absolute ethanol and treated with etherealhydrogen chloride. The solvent was evaporated, and the residue was takenup in hot 2-propanol and chilled. The precipitate was collected andrecrystallized twice from absolute ethanol/ether to give 2.1 g (53%) ofproduct, mp 140°-145° C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.24 H.sub.32 Cl.sub.3 N.sub.5 O.sub.2 :                                   54.50% C  6.10% H  13.24% N                                   Found:          53.86% C  6.44% H  12.93% N                                   ______________________________________                                    

EXAMPLE 21

1-{1-4-(2-Aminoethoxyimino)-4-phenylbutyl!-4-piperidinyl}-1,3-dihydro-2-benzimidazolonedihydrochloride

A mixture of 1-1-(4-oxo-4-phenylbutyl)-4-piperidinyl!-1,3-dihydro-2-benzimidazolone(3.85 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.89 g), 3equivalents of pyridine, and absolute ethanol (75 mil) was heated underreflux, under nitrogen, with stirring, for three hrs. The reactionmixture was partitioned between 10% sodium hydroxide solution and ethylacetate. The layers were separated and the aqueous phase extracted withethyl acetate. The combined organic extracts were dried over anhydroussodium sulfate, filtered, aid the filtrate was evaporated. The residuewas taken up ill toluene and evaporated. The residue was purified byflash chromatography (180:19:1 dichloromethane/methanol/ammoniumhydroxide). The appropriate fractions were collected and evaporated. Theresidue was dissolved in absolute ethanol and treated with etherealhydrogen chloride. The solvent was evaporated and the residue was takenup in hot 2-propanol and chilled. The precipitate was collected andrecrystallized from 2-propanol and then twice from ethanol/ether to give1.5 g (29%) of product, mp 175°-180° C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.24 H.sub.33 Cl.sub.2 N.sub.5 O.sub.2 :                                   58.30% C  6.73% H  14.16% N                                   Found:          57.73% C  6.93% H  13.83% N                                   ______________________________________                                    

EXAMPLE 22

Cyclopropyl- 4-(2-phenyl-1-imidazolyl)phenyl!methanoneO-(2-aminioethyl)oxime dihydrochloride

A mixture of cyclopropyl-14-(2-phenyl-1-imidazolyl)phenyl!methanone (2.6g), aminoethylhydroxylamine dihydrochloride (1.95 g), and 3 equivalentsof pyridine, in absolute ethanol (30 ml) was heated under reflux, undernitrogen, with stirring, overnight. The reaction mixture was evaporated,the residue was taken up in ethyl acetate and washed with a 10% sodiumhydroxide solution. The organic extracts were evaporated and the residuepurified by high performance liquid chromatography (silica gel, 185:14:1dichloromethane/methanol/ammonium hydroxide). The appropriate fractionswere collected and concentrated. The residue was taken up in ethanol andtreated with ethereal hydrogen chloride. The mixture was evaporated. Theresidue was recrystallized from ethanol/ether to give 3.06 g (80.9%) ofproduct, mp>220° C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.21 H.sub.24 Cl.sub.2 N.sub.4 O.sub.2 :                                   60.15% C  5.77% H  13.36% N                                   Found:          60.18% C  6.06% H  13.20% N                                   ______________________________________                                    

EXAMPLE 23

Cyclopropyl- 4-(2-phenyl-1-imidazolyl)phenyl!methanone

A solution of 4-chloro-4'-fluorobutyrophenone (15.0 g) and2-phenylimidazole (100 mL) in dry dimethylformamide was heated, undernitrogen, at 150° C., with stirring, overnight. The reaction mixture wascooled, diluted with water and extracted with ethyl acetate. The organicextracts were evaporated and the residue was purified by highperformance liquid chromatography (silica gel, dichloromethane to 1%methanol/dichloromethane). The appropriate fractions were collected andconcentrated. The residue was recrystallized from ethanol to give 4.3 g(19.9%) of product, mp 155°-157° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.19 H.sub.16 N.sub.2 O:                                                 79.14% C   5.59% H  9.71% N                                     Found:        79.03% C   5.49% H  9.72% N                                     ______________________________________                                         ##STR19##                                                                 

We claim:
 1. A compound of the formulawherein Y is hydrogen orloweralkyl and p is 1 or
 2. 2. The compound according to claim 1 whichis cyclopropyl- 4-(2-phenyl-1-imidazolyl)phenyl!methanone.